The independent associations of HbA1c, C-reactive protein and birth weight with cardiovascular disease, diabetes mellitus and chronic kidney disease in a remote Indigenous Australian community: a prospective cohort study

Abstract

Background: Chronic diseases account for a significant portion of the life expectancy disparity between Indigenous and non-Indigenous Australians. Indigenous Australians have high rates of chronic kidney disease (CKD), cardiovascular disease (CVD) and diabetes, however the long term association of many risk factors is yet to be completely understood. Risk markers such as birth weight (BW), C-reactive protein (CRP) and glycosylated haemoglobin (HbA1c) play a significant role in the chronic disease burden however more evidence is required in Indigenous Australian communities to highlight the true impacts of the associations. Furthermore, the appropriateness of HbA1c as a marker of diabetes in remote Indigenous Australians has not been sufficiently investigated. Aims: This thesis aims to investigate HbA1c as a marker of risk for diabetes and CVD, and the associations between BW and CVD, CRP and CKD in numerous secondary projects for a remote Indigenous Australian community. Methods: The projects investigating BW and CRP, as risk factors, utilised community-wide health screening examinations conducted in 1992-1999, while projects that investigated associations with HbA1c used data from screening examinations conducted in 2004-2006. Northern Territory hospitalisation records between 1992 and 2012 were utilised to follow participants for up to 20 years after baseline exams. Cox proportional hazard models were used to investigate the long term associations between BW and CVD, and CRP and CKD. Logistic regression models were used for analysis between HbA1c and diabetes. Results: A total of 1187, 852, and 546 participants were included in the HbA1c, LBW and CRP projects, respectively. Of the 1187 HbA1c participants, 158 (13 %) had a previous diabetes diagnosis, up to 568 (48 %) were at high risk (5.7-6.4 % (39-46 mmol/mol) HbA1c) and 67 (6 %) potential new cases of diabetes (≥ 6.5 % (48 mmol/mol) HbA1c) were identified. Almost all traditional cardiovascular disease risk factors showed a positive association with levels of HbA1c. In our study population, there were 236 (28 %) participants who had a low birth weight. The LBW group had a higher risk of developing any CVD (HR = 1.43, 95% CI 1.01-2.03), major CVD (HR = 1.51, 95% CI 0.93-2.47) and hypertension (HR = 1.83, 95% CI 1.09-2.96) than the normal birth weight (NBW) (≥2,500 g) group. Women with LBW had over 2.6 times the risk of a hospitalisation associated with hypertension compared to their NBW counterparts (HR = 2.61, 95% CI 1.38-4.93), but this relationship was not seen in men. The risk for CVD significantly increased for adults with high waist circumference (WC) and low BW more than any other group (RR 7.22, 95 % CI 1.96-26.64, p = 0.003). Participants in the highest CRP tertile had almost 4 times the risk for CKD hospitalisations compared with participants in the lowest tertile (HR=3.91, 95% CI 1.01-15.20, p=0.049) after adjustment for potential confounding factors. Participants with CRP concentrations greater than 3mg/L had almost 3 times the risk of CKD hospitalisations than those ≤ 3mg/L (HR=2.84, 95% CI 1.00-8.00, p=0.049). Furthermore, risk for CKD increased 34% per doubled increase in CRP (HR=1.34, 95% CI 1.04-1.74, p=0.024). Conclusions: This thesis identified that HbA1c, BW and CRP are significant markers of risk for chronic disease in this remote Indigenous Australian community. LBW increased the risk of cardiovascular disease hospitalisations in adult life and this risk is increased if the LBW individual grows to have a large WC in adult life. The glycosylated haemoglobin screening in this community highlighted the high proportion of individuals living at high risk for diabetes and with an accentuated cardiovascular risk profile. C-reactive protein was found to be an independent predictor of CKD hospitalisations almost a decade later in life. Further investigations into the biological mechanisms of the associations are necessary, because this was not within the scope of this thesis. This thesis provides much needed evidence using longitudinal cohort data demonstrating a long term association between these risk factors and chronic disease development up to 20 years later in life.